VX765 Attenuates Pyroptosis and HMGB1/TLR4/NF-κB Pathways to Improve Functional Outcomes in TBI Mice

Abstract

Background. Traumatic brain injury (TBI) refers to temporary or permanent damage to brain function caused by penetrating objects or blunt force trauma. TBI activates inflammasome-mediated pathways and other cell death pathways to remove inactive and damaged cells, however, they are also harmful to the central nervous system. The newly discovered cell death pattern termed pyroptosis has become an area of interest. It mainly relies on caspase-1-mediated pathways, leading to cell death. Methods. Our research focus is VX765, a known caspase-1 inhibitor which may offer neuroprotection after the process of TBI. We established a controlled cortical impact (CCI) mouse model and then controlled the degree of pyroptosis in TBI with VX765. The effects of caspase-1 inhibition on inflammatory response, pyroptosis, blood-brain barrier (BBB), apoptosis, and microglia activation, in addition to neurological deficits, were investigated. Results. We found that TBI led to NOD-like receptors (NLRs) as well as absent in melanoma 2 (AIM2) inflammasome-mediated pyroptosis in the damaged cerebral cortex. VX765 curbed the expressions of indispensable inflammatory subunits (caspase-1 as well as key downstream proinflammatory cytokines such as interleukin- (IL-) 1β and IL-18). It also inhibited gasdermin D (GSDMD) cleavage and apoptosis-associated spot-like protein (ASC) oligomerization in the injured cortex. In addition to the above, VX765 also inhibited the inflammatory activity of the high-mobility cassette -1/Toll-like receptor 4/nuclear factor-kappa B (HMGB1/TLR4/NF-kappa B) pathway. By inhibiting pyroptosis and inflammatory mediator expression, we demonstrated that VX765 can decrease blood-brain barrier (BBB) leakage, apoptosis, and microglia polarization to exhibit its neuroprotective effects. Conclusion. In conclusion, VX765 can counteract neurological damage after TBI by reducing pyroptosis and HMGB1/TLR4/NF-κB pathway activities. VX765 may have a good therapeutic effect on TBI.

Dimethyl itaconate inhibits LPS‑induced microglia inflammation and inflammasome‑mediated pyroptosis via inducing autophagy and regulating the Nrf‑2/HO‑1 signaling pathway

“…In the present study, external administration of DI effectively reduced NLRP3 inflammasome activation and subsequently inhibited NLRP3-mediated GSDMD cleavage, further emphasizing the inhibitory effect of DI on pyroptosis. The previous studies performed by our group highlighted the importance of inhibiting the NLRP3 inflammasome in order to achieve neural functional recovery from traumatic injury and ischemia stroke ( 41 – 43 ). DI may possess significant potential as a neuropathological drug for promoting neurological functional recovery due to its strong inhibitory activity against NLRP3-mediated pathways.…”

Atorvastatin ameliorates early brain injury after subarachnoid hemorrhage via inhibition of pyroptosis and neuroinflammation

“…The nucleotide‐binding oligomerization domain (NOD)‐like receptor (NLR) pyrin domain‐containing (NLRP) inflammasomes activate the cleavage of pro‐interleukin‐1β (pro‐IL‐1β) and pro‐IL‐18, based on caspase‐1 and trigger pyroptosis (Huang et al, 2020). Recently, it was reported that pyroptosis is widespread in diseases of the central nervous system, which is involved in the repair, aging, tumor, cerebral hemorrhage, and ischemia of the central nervous system (Huang et al, 2020; Q. Li et al, 2020; Sun et al, 2020). However, the precise role of pyroptosis and related regulation drugs in SAH has not been confirmed.…”

Autophagic Degradation of Gasdermin D Protects against Nucleus Pulposus Cell Pyroptosis and Retards Intervertebral Disc Degeneration In Vivo

“…To further investigate the role of autophagy and pyroptosis in IDD, a rat disc IDD model was designed and conducted by needle puncture. VX-765, a caspase-1 inhibitor, which could efficiently decrease cell pyroptosis, was used in our animal model [ 27 ]. Degenerative NP tissues were marked by loss of ECM proteins and replaced by fibrous tissues.…”